We are studying the secretin-VIP family of G-protein coupled receptors. This recently identified group of receptors has virtually no amino acid sequence conservation with the remaining majority of G-protein coupled receptors (the rhodopsin family). Much less is known about structure- function relationships and effector system coupling of the secretin-VIP family receptors. Their cloning has also raised new questions about their physiological roles and created tools for study of their distribution, regulation and pharmacology. Previously we identified the receptor for GIP. This has facilitated the study of GIP's involvement in peripheral glucose homeostasis. Our collaborator Mike Wolfe (Gastroenterology Div. Brigham and Womens Hospital) used a GIP reporter cell we generated to develop a GIP receptor antagonist and used this antagonist to demonstrate in rats that GIP is a major mediator of the immediate insulin response to feeding. We recently discovered a new receptor which recognizes parathyroid hormone, which we have named the PTH2 receptor. We have now further characterized the pharmacological properties of the PTH2 receptor and studied its distribution. In collaboration with the Endocrine Unit at Mass. General Hospital we identified the amino acid residues in parathyroid hormone-related peptide (PTHrP) which allow the PTH2 receptor to discriminate between PTH and PTHrP. Mapping the distribution of PTH2 receptor mRNA suggests that it may play a role in a number of physiological systems including blood pressure control. In the CNS it appears to be present in hippocampal input and output circuits. We have preliminary evidence for a new bioactive peptide in brain extracts which acts at the PTH2 receptor and are now working on a detailed characterization and purification of that peptide.